Possible mechanisms of action of clarithromycin and its clinical application as a repurposing drug for treating multiple myeloma

Abstract

Clarithromycin (CAM), a semisynthetic macrolide antibiotic, is a widely used antibacterial drug. Recently, the efficacy of CAM as an add-on drug for treating multiple myeloma (MM) has been noted. Its effect on treating MM has been confirmed in combination chemotherapies that include CAM. However, a single treatment of CAM has no efficacy for treating MM. Many myeloma growth factors (MGFs) including interleukin (IL)-6 are known to be closely involved in the development of MM. CAM has been shown to suppress many MGFs, particularly IL-6. The possible mechanisms of action of CAM in treating MM have been suggested to include its immunomodulatory effect, autophagy inhibition, reversibility of drug resistance, steroid-sparing/enhancing effect and suppression of MGFs. In addition, MM is characterised by uncontrolled cell growth of monoclonal immunoglobulin (Ig)-producing neoplastic plasma cells. Large quantities of unfolded or misfolded Ig production may trigger considerable endoplasmic reticulum stress. Thus, MM is originally a fragile neoplasm particularly susceptible to autophagy-, proteasomeand histone deacetylase 6-inhibitors. Taken together, CAM plays an important role in MM treatments through its synergistic mechanisms. In addition, CAM with its pleiotropic effects on cytokines including IL-6 and indirect antiviral effects might be worth a try for treating COVID-19.

Diverse effects of clarithromycin and proposal of its clinical application for treating COVID-19 as a repurposing drug

“…Basic patterns of the effects of CAM and AZM on immunological markers seem to be almost similar (LeBel, 1993). In contrast to AZM, CAM has diverse effects (LeBel, 1993;C v ulić , 2001;Kanoh & Rubin, 2010;Van Nuffel et al, 2015;Takemori et al, 2020) and is more effective in suppressing cytokine production than AZM (Pathak et al, 2014). AZM is pharmacologically very similar to CAM, but, according to our clinical experience and scientific literature, CAM as an antiviral, anti-inflammatory and/or immunomodulatory drug seems to be much better (Mansilla et al, 2020).…”

“…Cai et al (2013) investigated whether alveolar macrophages produce aberrant pro-inflammatory cytokines in bronchiolitis obliterans organizing pneumonia (BOOP) and whether this can be inhibited by CAM or AZM. They demonstrated that spontaneous and lipopolysaccharidestimulated alveolar macrophages from patients with BOOP showed an increase in the production of TNF-α, soluble TNF receptor 1 (TNFR1) and TNFR2, IL-1β, IL-6, IL-8, IL-10, IFN-γ-inducible protein (IP-10) and CC chemokine ligand It should be noted that CAM represents a potent inhibitor of IL-6, TNF-α and IL-1, which are the three major cytokines responsible for inflammation (Takemori et al, 2020).…”

“…The common adverse effects of CAM are diarrhea, nausea, abnormal taste, dyspepsia, abdominal pain/discomfort, headache, insomnia, tooth discoloration, smell loss and taste loss, liver dysfunction, somnolence, confusion, allergic reactions ranging from urticaria and mild skin eruptions to anaphylaxis, Steven-Johnson syndrome and toxic epidermal necrosis, (LeBel, 1993;C v ulić , 2001;Kanoh & Rubin, 2010;FDA, 2015;Van Nuffel et al, 2015;Takemori et al, 2020). Most of these adverse effects are usually mild in intensity and resolve after the discontinuation of treatment.…”

“…CAM is a unique macrolide antibiotic which has diverse effects as compared to other macrolides. It includes immunomodulatory and immunosuppressive effects, autophagy inhibition, steroid sparing effect, reversibility of drug resistance, antineoplastic effect, antiviral effect as well as bacteriostatic/bactericidal effect (LeBel, 1993;C v ulić et al, 2001;Kanoh & Rubin, 2010;Van Nuffel et al, 2015;Takemori et al, 2020). Thus far, we have investigated the effect of CAM on multiple myeloma.…”

“…Thus far, we have investigated the effect of CAM on multiple myeloma. During that study, we noticed that CAM could also be applied for the treatment of COVID-19 (Takemori et al, 2020). It is well known that the antibacterial effect of macrolides, including CAM, is related to their ability to inhibit protein synthesis by binding to the subunit 50S of the bacterial ribosome (Poehlsgaard & Douthwaite, 2002).…”